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Background <p>Trastuzumab resistance in HER2-positive cancers remains a significant clinical challenge with limited therapeutic options. Although the tumor-promoting role of the Yes-associated protein (YAP) pathway is well established, its role in trastuzumab resistance remains unclear. </p> Methods <p>We established four trastuzumab-resistant (HR) cell lines (NCI-N87HR, SNU216HR, SNU2670HR, and SNU2773HR) from HER2-positive gastric cancer and biliary tract cancer cell lines. YAP pathway activation was assessed using Phospho-RTK arrays, bulk RNA-Seq, and immunofluorescence. Antitumor effects of YAP targeting were evaluated with MTT assays, cell-cycle analysis, migration assays, RT-qPCR, ELISA, and xenograft models of SNU-2773 and SNU-2773HR cells. Immune modulation by YAP was studied through co-culture experiments with human PBMCs and cancer cells, followed by flow cytometry analysis of immune markers.</p> Results <p>Upregulation and activation of the YAP/TAZ pathway were observed in HR cells, indicated by elevated ROR2 levels and nuclear translocation of YAP. This activation, driven by YAP/TEAD-dependent Wnt5a expression, suggests a positive-feedback mechanism that amplifies YAP activity. Elevated YAP and TEAD levels were observed in patient tumor tissues during disease progression following HER2-targeted therapies. Targeting YAP disrupted its oncogenic effects and restored sensitivity to trastuzumab, increased activation of CD4<sup>+</sup> and CD8<sup>+</sup> T cells in PBMCs, likely via PD-L1 downregulation and enhanced immunogenic cell death. Verteporfin, a YAP-TEAD inhibitor, effectively reduced tumor growth and increased apoptosis in mouse models bearing HR tumors.</p> Conclusions <p>Targeting the ROR2-YAP/TEAD axis presents a promising therapeutic approach to overcome trastuzumab resistance in HER2-positive cancers, offering a potential strategy for enhancing treatment efficacy and improving clinical outcomes.</p>

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YAP as a therapeutic target to reverse trastuzumab resistance

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月20日

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  • Ah-Rong Nam,
  • Kyoung-Seok Oh,
  • Ju-Hee Bang,
  • Yoojin Jeong,
  • Sea Young Choo,
  • Hyo Jung Kim,
  • Su In Lee,
  • Jae-Min Kim,
  • Jeesun Yoon,
  • Tae-Yong Kim,
  • Do-Youn Oh

摘要

Background

Trastuzumab resistance in HER2-positive cancers remains a significant clinical challenge with limited therapeutic options. Although the tumor-promoting role of the Yes-associated protein (YAP) pathway is well established, its role in trastuzumab resistance remains unclear.

Methods

We established four trastuzumab-resistant (HR) cell lines (NCI-N87HR, SNU216HR, SNU2670HR, and SNU2773HR) from HER2-positive gastric cancer and biliary tract cancer cell lines. YAP pathway activation was assessed using Phospho-RTK arrays, bulk RNA-Seq, and immunofluorescence. Antitumor effects of YAP targeting were evaluated with MTT assays, cell-cycle analysis, migration assays, RT-qPCR, ELISA, and xenograft models of SNU-2773 and SNU-2773HR cells. Immune modulation by YAP was studied through co-culture experiments with human PBMCs and cancer cells, followed by flow cytometry analysis of immune markers.

Results

Upregulation and activation of the YAP/TAZ pathway were observed in HR cells, indicated by elevated ROR2 levels and nuclear translocation of YAP. This activation, driven by YAP/TEAD-dependent Wnt5a expression, suggests a positive-feedback mechanism that amplifies YAP activity. Elevated YAP and TEAD levels were observed in patient tumor tissues during disease progression following HER2-targeted therapies. Targeting YAP disrupted its oncogenic effects and restored sensitivity to trastuzumab, increased activation of CD4+ and CD8+ T cells in PBMCs, likely via PD-L1 downregulation and enhanced immunogenic cell death. Verteporfin, a YAP-TEAD inhibitor, effectively reduced tumor growth and increased apoptosis in mouse models bearing HR tumors.

Conclusions

Targeting the ROR2-YAP/TEAD axis presents a promising therapeutic approach to overcome trastuzumab resistance in HER2-positive cancers, offering a potential strategy for enhancing treatment efficacy and improving clinical outcomes.